Limits...
Efficacy of recombinant human interleukin 7 in a patient with severe lymphopenia-related progressive multifocal leukoencephalopathy.

Gasnault J, de Goër de Herve MG, Michot JM, Hendel-Chavez H, Seta V, Mazet AA, Croughs T, Stankoff B, Bourhis JH, Lambotte O, Delfraissy JF, Taoufik Y - Open Forum Infect Dis (2014)

Bottom Line: In this study, we report the case of a patient with profound lymphopenia after allogenic bone marrow transplantation who developed severe progressive multifocal leukoencephalopathy.Single-agent recombinant human interleukin-7 therapy was associated with restoration of anti-John Cunningham polyomavirus (JCV) T-cell responses, JCV clearance from cerebrospinal fluid, and a dramatic clinical improvement.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine , Assistance Publique-Hôpitaux de Paris (AP -HP), Hôpital Bicêtre , Le Kremlin-Bicêtre , France ; Institut National de la Santé et de la Recherche Médicale (INSERM) U1012, Faculté de Médecine , Université Paris Sud , Le Kremlin-Bicêtre , France.

ABSTRACT
In this study, we report the case of a patient with profound lymphopenia after allogenic bone marrow transplantation who developed severe progressive multifocal leukoencephalopathy. Single-agent recombinant human interleukin-7 therapy was associated with restoration of anti-John Cunningham polyomavirus (JCV) T-cell responses, JCV clearance from cerebrospinal fluid, and a dramatic clinical improvement.

No MeSH data available.


Related in: MedlinePlus

Magnetic resonance (MR) images, neurological score, and immunovirological parameters. A and B show T2-weighted and T1-weighted MR images 2 weeks before recombinant human interleukin-7 (rhIL-7) treatment. C and D show T2-weighted and T1-weighted MR images 18 months after rhIL-7 treatment. E shows the time course of the progressive multifocal leukoencephalopathy neurological score9 after the 3 injections of rhIL-7 (green arrows). F shows the CD4 T-cell count (top), CD8 T-cell count (middle), and CD4/CD8 T-cell ratio (bottom) at various times after the 3 IL-7 injections (green arrows). G shows the distribution of CD4 and CD8 T-cell subsets determined by flow cytometry the day before the first rIL-7 injection and at the posttreatment peak blood CD4 T-cell count (day 14): TCM, central memory T cells (CD45RA− CCR7+ CD4+ CD3+); TEM, effector memory T cells (CD45RA− CCR7− CD4+ CD3+); TN, naive T cells (CD45RA+ CCR7+ CD4+ CD3+); TEFF, effector T cells (CD45RA+ CCR7− CD4+ CD3+). (H), JC virus (JCV) load in cerebrospinal fluid was measured by quantitative polymerase chain reaction with a detection limit of 125 copies/mL [9]. I shows proliferative CD4 T-cell responses to purified JCV (MAD-4 strain, ATCC) after 6 days of exposure [9, 10]. Proliferation was measured by means of 3H-thymidine incorporation [9, 10]. Results (gray dots) are expressed as median counts per min (CPM) of activated wells (in quadruplicate) minus median CPM in untreated wells (corrected CPM). With the exception of day 0, all JCV-specific CD4 T-cell proliferative responses were positive. Criteria of positivity were previously published [9]. Peripheral blood mononuclear cells (PBMCs) were also stimulated overnight with a pool of JCV peptides overlapping JCV VP1 protein, and interferon-γ secretion was measured with an enzyme-linked immunospot assay performed in duplicate (black dots) [9, 11]. Results are expressed as mean spots per 106 activated PBMCs minus the mean spots obtained in untreated wells (corrected spots). The threshold of positivity was 40 spots per 106 PBMCs [10] (red line in I). Abbreviations: CSF, cerebrospinal fluid; IFN, interferon; PML, progressive multifocal leukoencephalopathy.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4281783&req=5

OFU074F1: Magnetic resonance (MR) images, neurological score, and immunovirological parameters. A and B show T2-weighted and T1-weighted MR images 2 weeks before recombinant human interleukin-7 (rhIL-7) treatment. C and D show T2-weighted and T1-weighted MR images 18 months after rhIL-7 treatment. E shows the time course of the progressive multifocal leukoencephalopathy neurological score9 after the 3 injections of rhIL-7 (green arrows). F shows the CD4 T-cell count (top), CD8 T-cell count (middle), and CD4/CD8 T-cell ratio (bottom) at various times after the 3 IL-7 injections (green arrows). G shows the distribution of CD4 and CD8 T-cell subsets determined by flow cytometry the day before the first rIL-7 injection and at the posttreatment peak blood CD4 T-cell count (day 14): TCM, central memory T cells (CD45RA− CCR7+ CD4+ CD3+); TEM, effector memory T cells (CD45RA− CCR7− CD4+ CD3+); TN, naive T cells (CD45RA+ CCR7+ CD4+ CD3+); TEFF, effector T cells (CD45RA+ CCR7− CD4+ CD3+). (H), JC virus (JCV) load in cerebrospinal fluid was measured by quantitative polymerase chain reaction with a detection limit of 125 copies/mL [9]. I shows proliferative CD4 T-cell responses to purified JCV (MAD-4 strain, ATCC) after 6 days of exposure [9, 10]. Proliferation was measured by means of 3H-thymidine incorporation [9, 10]. Results (gray dots) are expressed as median counts per min (CPM) of activated wells (in quadruplicate) minus median CPM in untreated wells (corrected CPM). With the exception of day 0, all JCV-specific CD4 T-cell proliferative responses were positive. Criteria of positivity were previously published [9]. Peripheral blood mononuclear cells (PBMCs) were also stimulated overnight with a pool of JCV peptides overlapping JCV VP1 protein, and interferon-γ secretion was measured with an enzyme-linked immunospot assay performed in duplicate (black dots) [9, 11]. Results are expressed as mean spots per 106 activated PBMCs minus the mean spots obtained in untreated wells (corrected spots). The threshold of positivity was 40 spots per 106 PBMCs [10] (red line in I). Abbreviations: CSF, cerebrospinal fluid; IFN, interferon; PML, progressive multifocal leukoencephalopathy.

Mentions: The patient presented with neurological symptoms in February 2012 and gradually developed left brachiofacial paresthesia. Computed tomography (CT) of the brain showed 2 hypodense white-matter lesions in the right hemisphere, whereas magnetic resonance imaging (MRI) revealed multiple subcortical white-matter lesions (hyperintense on T2-weighted images, hypointense on T1-weighted images, with no gadolinium enhancement) in the right frontal and parietal lobes. The lesions were consistent with demyelination and suggestive of PML (data not shown). Polymerase chain reaction (PCR) revealed JCV DNA in CSF (360 copies/mL), confirming the diagnosis of PML. The patient had been JCV-seropositive before bone marrow grafting (STRATIFY JCV Antibody, Focus Diagnostics). At PML onset, she had moderate lymphopenia (902/µL) but severe CD4 T-cell lymphopenia (135/µL) and a normal absolute CD8 T-cell count (CD4/CD8 ratio: 0.37). The immunoglobulin G level was normal (11.2 g/L). Human immunodeficiency virus serostatus determined before (January 2011) and after (May 2011, August 2011, and June 2012) bone marrow transplantation was negative. Thoracic CT performed for nonproductive cough with fever showed an interstitial syndrome. Bronchial lavage revealed Pneumocystis jiroveci cysts (prophylaxis with pyrimethamine-sulfadoxine and pentamidine was stopped in February 2012), and she was treated with atovaquone. She became afebrile 3 days later but rapidly developed progressive left-sided sensory-motor impairment. Physical examination showed severe hemiparesis (rating 1/5) with multimodal sensory impairment on the left side of the body. Her neurological status rapidly worsened, with the onset of swallowing disorders and dysarthria, and she became totally bedridden. Myoclonus occurred in the left upper limb but resolved, without recurrence, after the introduction of levetiracetam. Magnetic resonance imaging performed on 14 March 2012 showed progression of the brain lesions (Figure 1A and B).Figure 1.


Efficacy of recombinant human interleukin 7 in a patient with severe lymphopenia-related progressive multifocal leukoencephalopathy.

Gasnault J, de Goër de Herve MG, Michot JM, Hendel-Chavez H, Seta V, Mazet AA, Croughs T, Stankoff B, Bourhis JH, Lambotte O, Delfraissy JF, Taoufik Y - Open Forum Infect Dis (2014)

Magnetic resonance (MR) images, neurological score, and immunovirological parameters. A and B show T2-weighted and T1-weighted MR images 2 weeks before recombinant human interleukin-7 (rhIL-7) treatment. C and D show T2-weighted and T1-weighted MR images 18 months after rhIL-7 treatment. E shows the time course of the progressive multifocal leukoencephalopathy neurological score9 after the 3 injections of rhIL-7 (green arrows). F shows the CD4 T-cell count (top), CD8 T-cell count (middle), and CD4/CD8 T-cell ratio (bottom) at various times after the 3 IL-7 injections (green arrows). G shows the distribution of CD4 and CD8 T-cell subsets determined by flow cytometry the day before the first rIL-7 injection and at the posttreatment peak blood CD4 T-cell count (day 14): TCM, central memory T cells (CD45RA− CCR7+ CD4+ CD3+); TEM, effector memory T cells (CD45RA− CCR7− CD4+ CD3+); TN, naive T cells (CD45RA+ CCR7+ CD4+ CD3+); TEFF, effector T cells (CD45RA+ CCR7− CD4+ CD3+). (H), JC virus (JCV) load in cerebrospinal fluid was measured by quantitative polymerase chain reaction with a detection limit of 125 copies/mL [9]. I shows proliferative CD4 T-cell responses to purified JCV (MAD-4 strain, ATCC) after 6 days of exposure [9, 10]. Proliferation was measured by means of 3H-thymidine incorporation [9, 10]. Results (gray dots) are expressed as median counts per min (CPM) of activated wells (in quadruplicate) minus median CPM in untreated wells (corrected CPM). With the exception of day 0, all JCV-specific CD4 T-cell proliferative responses were positive. Criteria of positivity were previously published [9]. Peripheral blood mononuclear cells (PBMCs) were also stimulated overnight with a pool of JCV peptides overlapping JCV VP1 protein, and interferon-γ secretion was measured with an enzyme-linked immunospot assay performed in duplicate (black dots) [9, 11]. Results are expressed as mean spots per 106 activated PBMCs minus the mean spots obtained in untreated wells (corrected spots). The threshold of positivity was 40 spots per 106 PBMCs [10] (red line in I). Abbreviations: CSF, cerebrospinal fluid; IFN, interferon; PML, progressive multifocal leukoencephalopathy.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4281783&req=5

OFU074F1: Magnetic resonance (MR) images, neurological score, and immunovirological parameters. A and B show T2-weighted and T1-weighted MR images 2 weeks before recombinant human interleukin-7 (rhIL-7) treatment. C and D show T2-weighted and T1-weighted MR images 18 months after rhIL-7 treatment. E shows the time course of the progressive multifocal leukoencephalopathy neurological score9 after the 3 injections of rhIL-7 (green arrows). F shows the CD4 T-cell count (top), CD8 T-cell count (middle), and CD4/CD8 T-cell ratio (bottom) at various times after the 3 IL-7 injections (green arrows). G shows the distribution of CD4 and CD8 T-cell subsets determined by flow cytometry the day before the first rIL-7 injection and at the posttreatment peak blood CD4 T-cell count (day 14): TCM, central memory T cells (CD45RA− CCR7+ CD4+ CD3+); TEM, effector memory T cells (CD45RA− CCR7− CD4+ CD3+); TN, naive T cells (CD45RA+ CCR7+ CD4+ CD3+); TEFF, effector T cells (CD45RA+ CCR7− CD4+ CD3+). (H), JC virus (JCV) load in cerebrospinal fluid was measured by quantitative polymerase chain reaction with a detection limit of 125 copies/mL [9]. I shows proliferative CD4 T-cell responses to purified JCV (MAD-4 strain, ATCC) after 6 days of exposure [9, 10]. Proliferation was measured by means of 3H-thymidine incorporation [9, 10]. Results (gray dots) are expressed as median counts per min (CPM) of activated wells (in quadruplicate) minus median CPM in untreated wells (corrected CPM). With the exception of day 0, all JCV-specific CD4 T-cell proliferative responses were positive. Criteria of positivity were previously published [9]. Peripheral blood mononuclear cells (PBMCs) were also stimulated overnight with a pool of JCV peptides overlapping JCV VP1 protein, and interferon-γ secretion was measured with an enzyme-linked immunospot assay performed in duplicate (black dots) [9, 11]. Results are expressed as mean spots per 106 activated PBMCs minus the mean spots obtained in untreated wells (corrected spots). The threshold of positivity was 40 spots per 106 PBMCs [10] (red line in I). Abbreviations: CSF, cerebrospinal fluid; IFN, interferon; PML, progressive multifocal leukoencephalopathy.
Mentions: The patient presented with neurological symptoms in February 2012 and gradually developed left brachiofacial paresthesia. Computed tomography (CT) of the brain showed 2 hypodense white-matter lesions in the right hemisphere, whereas magnetic resonance imaging (MRI) revealed multiple subcortical white-matter lesions (hyperintense on T2-weighted images, hypointense on T1-weighted images, with no gadolinium enhancement) in the right frontal and parietal lobes. The lesions were consistent with demyelination and suggestive of PML (data not shown). Polymerase chain reaction (PCR) revealed JCV DNA in CSF (360 copies/mL), confirming the diagnosis of PML. The patient had been JCV-seropositive before bone marrow grafting (STRATIFY JCV Antibody, Focus Diagnostics). At PML onset, she had moderate lymphopenia (902/µL) but severe CD4 T-cell lymphopenia (135/µL) and a normal absolute CD8 T-cell count (CD4/CD8 ratio: 0.37). The immunoglobulin G level was normal (11.2 g/L). Human immunodeficiency virus serostatus determined before (January 2011) and after (May 2011, August 2011, and June 2012) bone marrow transplantation was negative. Thoracic CT performed for nonproductive cough with fever showed an interstitial syndrome. Bronchial lavage revealed Pneumocystis jiroveci cysts (prophylaxis with pyrimethamine-sulfadoxine and pentamidine was stopped in February 2012), and she was treated with atovaquone. She became afebrile 3 days later but rapidly developed progressive left-sided sensory-motor impairment. Physical examination showed severe hemiparesis (rating 1/5) with multimodal sensory impairment on the left side of the body. Her neurological status rapidly worsened, with the onset of swallowing disorders and dysarthria, and she became totally bedridden. Myoclonus occurred in the left upper limb but resolved, without recurrence, after the introduction of levetiracetam. Magnetic resonance imaging performed on 14 March 2012 showed progression of the brain lesions (Figure 1A and B).Figure 1.

Bottom Line: In this study, we report the case of a patient with profound lymphopenia after allogenic bone marrow transplantation who developed severe progressive multifocal leukoencephalopathy.Single-agent recombinant human interleukin-7 therapy was associated with restoration of anti-John Cunningham polyomavirus (JCV) T-cell responses, JCV clearance from cerebrospinal fluid, and a dramatic clinical improvement.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine , Assistance Publique-Hôpitaux de Paris (AP -HP), Hôpital Bicêtre , Le Kremlin-Bicêtre , France ; Institut National de la Santé et de la Recherche Médicale (INSERM) U1012, Faculté de Médecine , Université Paris Sud , Le Kremlin-Bicêtre , France.

ABSTRACT
In this study, we report the case of a patient with profound lymphopenia after allogenic bone marrow transplantation who developed severe progressive multifocal leukoencephalopathy. Single-agent recombinant human interleukin-7 therapy was associated with restoration of anti-John Cunningham polyomavirus (JCV) T-cell responses, JCV clearance from cerebrospinal fluid, and a dramatic clinical improvement.

No MeSH data available.


Related in: MedlinePlus